Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

NCT02359565 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: NCI-2015-00130PBTC-045UM1CA081457
• Study Type: interventional
• Target: 71
• Locations: 2 countries
• Sites: 12

Brief Summary

This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.

Conditions

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Refractory Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Medulloblastoma; Recurrent Diffuse Intrinsic Pontine Glioma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events

  Will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events observed during the dose finding period as well as during later courses will be summarized by stratum and by dose (if applicable). Separate tables for adverse events attributable to pembrolizumab will also be provided for each of the five strata.

  Within 30 days of treatment

• Sustained objective response (partial response + complete response)

  Stratum specific exact confidence interval estimates will be provided for the sustained objective response rates. In addition, if adequate number of responses is observed to make such analyses meaningful, stratum-specific confirmed sustained objective response rates observed during treatment will be estimated by cumulative incidence functions.

  Within 12 cycles (approximately 9 months)

• Change in the percentage of CD8+ T cells that are PD-1+ due to treatment with pembrolizumab (Stratum C)

  A 1-sample t-distribution-based confidence interval (or its non-parametric counterparts, as needed) will be used to estimate the average change in the percentage of CD8+ T cells that are PD-1+ due to treatment with pembrolizumab.

  Baseline to after 6 weeks of treatment

Secondary Outcomes (6)

• Progression-free survival (PFS)

  Date of initial treatment to the earliest date of disease progression or death from any cause for patients who fail and to the date of last contact for patients who remain at risk for failure, assessed bi-annually up to 3 years and then yearly thereafter

• Event-free survival

  Up to 3 years

• Overall survival (OS)

  Date of diagnosis to the earliest date of death from any cause or to the date of last contact for patients who remain at risk for failure, assessed bi-annually up to 3 years and then yearly thereafter

• Radiologic response (Stratum C)

  Up to 3 years

• Biomarker expression levels

  Up to 18 cycles (approximately 13.5 months)

Study Arms (1)

Treatment (pembrolizumab)

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 34 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo standard MRI, DCE permeability MRI, DTI, DSC perfusion MRI, MR diffusion imaging and may undergo MR spectroscopy as well as CSF and blood sample collection during screening and on study.

Procedure: Biospecimen Collection; Procedure: Conventional Magnetic Resonance Imaging; Procedure: Diffusion Tensor Imaging; Procedure: Diffusion Weighted Imaging; Procedure: Dynamic Contrast-enhanced MR Perfusion; Procedure: Dynamic Susceptibility Contrast-Perfusion-Weighted Imaging; Procedure: Magnetic Resonance Spectroscopic Imaging; Biological: Pembrolizumab

Interventions

Dynamic Susceptibility Contrast-Perfusion-Weighted Imaging PROCEDURE

Undergo DSC perfusion MRI

Also known as: DSC, DSC-PWI, Dynamic Susceptibility Contrast Perfusion Weighted Imaging, Dynamic Susceptibility Contrast Perfusion-Weighted MR Imaging, Dynamic Susceptibility Contrast-Enhanced MR Perfusion

Treatment (pembrolizumab)

Biospecimen Collection PROCEDURE

Undergo CSF and blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (pembrolizumab)

Conventional Magnetic Resonance Imaging PROCEDURE

Undergo standard MRI

Also known as: Conventional MRI

Treatment (pembrolizumab)

Diffusion Weighted Imaging PROCEDURE

Undergo MR diffusion imaging

Also known as: Diffusion Weighted MRI, Diffusion-Weighted Magnetic Resonance Imaging, Diffusion-Weighted MR Imaging, Diffusion-Weighted MRI, DW-MRI, DWI, DWI MRI, DWI-MRI, MR Diffusion-Weighted Imaging

Treatment (pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475

Treatment (pembrolizumab)

Diffusion Tensor Imaging PROCEDURE

Undergo DTI

Also known as: DIFFUSION TENSOR MRI, DT-MRI, DTI

Treatment (pembrolizumab)

Dynamic Contrast-enhanced MR Perfusion PROCEDURE

Undergo DCE permeability MRI

Also known as: DCE, DCE MR Perfusion, Dynamic Contrast-enhanced Magnetic Resonance Imaging Perfusion, Dynamic Contrast-enhanced MRI Perfusion, Permeability MRI

Treatment (pembrolizumab)

Magnetic Resonance Spectroscopic Imaging PROCEDURE

Undergo MR spectroscopy

Also known as: Magnetic Resonance Spectroscopy, MRS, MRS Imaging, MRSI, MS

Treatment (pembrolizumab)

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Tumor: patient must have one of the following diagnoses to be eligible:
• Stratum A, currently closed to enrollment: Patients must have a recurrent, progressive or refractory DIPG following radiation therapy with or without chemotherapy
• Histologic diagnosis is not required for patients with typical imaging findings of DIPG (defined as patients with a diffuse expansile mass centered in and involving at least 2/3 of the pons); patients with brainstem tumors who have undergone biopsy with a diagnosis of high-grade glioma or diffuse infiltrating glioma are also eligible
• Stratum B: Patients must have a histologically confirmed diagnosis of a non-brainstem high-grade glioma (NB-HGG) that is recurrent, progressive or refractory following therapy which included radiotherapy; spinal primary disease is eligible
• Stratum D: Patients must have a histologically confirmed diagnosis of ependymoma that is recurrent, progressive or refractory following therapy which included radiotherapy
• Stratum E: Patients must have a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive or refractory following therapy which included radiotherapy
• Patients must have adequate pre-trial formalin-fixed paraffin-embedded (FFPE) tumor material available for use in the biology studies mutational analysis and genome wide sequencing for each stratum
• Patients with DIPG who have tissue available are requested to submit similar tissue as patients in other strata; however, this is not required for eligibility
• All subjects must have measurable disease in 2-dimensions on MRI scan of the brain; disease should be consistently measured with the two largest perpendicular dimensions
• Patient must be \>= 1 but =\< 18 years of age at the time of enrollment during the safety portion. Patients \< 22 may be enrolled during the efficacy portion of the study.
• Patients must have received prior radiation therapy and/or chemotherapy and recovered from the acute treatment related toxicities (defined as =\< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study; there is no upper limit to the number of prior therapies that is allowed
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea
• Biologic or investigational agent (anti-neoplastic): Patient must have received their last dose of the investigational or biologic agent \>= 7 days prior to study enrollment
• For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration must be discussed with and approved by the study chair
• Monoclonal antibody treatment and/or agents with prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent \>= 28 days prior to study enrollment

You may not qualify if:

• Concurrent Illness
• Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except
• Patients with vitiligo or resolved asthma/atopy
• Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome
• History of or ongoing pneumonitis or significant interstitial lung disease Note: This would include non-infectious pneumonitis that required steroid use
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients with other current malignancies
• Patients with known hypermutated brain tumors including those with CMMRD and Lynch syndrome are ineligible for enrollment in Strata A, B, D and E
• Patients who have received a solid organ transplant
• Patients with bulky tumor on imaging are ineligible; treating physicians are encouraged to contact the study chair to request a rapid central imaging review to confirm fulfilment of these eligibility criteria, if they have concerns
• Bulk tumor is defined as:
• Tumor with evidence of clinically significant uncal herniation or midline shift
• Tumor with diameter of \> 5 cm in one dimension on T2/fluid attenuated inversion recovery (FLAIR)
• Tumor that in the opinion of the site investigator, shows significant mass effect in either the brain or spine
• Multi-focal/ metastatic disease:

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta - Arthur M Blank Hospital

Atlanta, Georgia, 30329, United States

Location

Lurie Children's Hospital-Chicago

Chicago, Illinois, 60611, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Saint Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

MeSH Terms

Conditions

Turcot syndrome; Colorectal Neoplasms, Hereditary Nonpolyposis; Glioma; Brain Neoplasms; Familial ependymoma; Diffuse Intrinsic Pontine Glioma; Medulloblastoma; Ependymoma

Interventions

Specimen Handling; Diffusion Tensor Imaging; Magnetic Resonance Spectroscopy; pembrolizumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Neoplastic Syndromes, Hereditary; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Stem Neoplasms; Infratentorial Neoplasms; Neuroectodermal Tumors, Primitive

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Neuroimaging; Diagnostic Imaging; Diffusion Magnetic Resonance Imaging; Magnetic Resonance Imaging; Tomography; Diagnostic Techniques, Neurological; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Eugene I Hwang

  Pediatric Brain Tumor Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 9, 2015
• First Posted: February 10, 2015
• Study Start: June 3, 2015
• Primary Completion: January 5, 2026
• Study Completion (Estimated): January 16, 2027
• Last Updated: April 13, 2026

Record last verified: 2026-01

Locations

CA (1); US (11)